Functional Divergence and Emerging Roles of the ANO-TMC-TMEM63 Channel Families in Olfaction and Gustation

The olfactory and gustatory systems are essential for survival, enabling organisms to detect and respond to environmental chemical cues. Although canonical signaling pathways in smell and taste have been well defined, growing evidence highlights additional ion channel families as key modulators of sensory responses. Recent studies identify the anoctamin, transmembrane channel-like, and TMEM63 superfamily as a class of non-canonical sensory effectors that regulate signal amplification, excitability, and epithelial homeostasis across chemosensory systems. In the mammalian olfactory epithelium, specific anoctamin channels enhance odor-evoked responses and contribute to tissue homeostasis. In the gustatory system, salt detection is now understood to involve multiple parallel signaling pathways, with TMC4 emerging as a key contributor to high-salt and salt-associated taste sensing. These channel families are evolutionarily conserved across species, including C. elegans, Drosophila, and aquatic organisms, where they mediate chemosensation, mechanosensation, humidity detection, and osmoregulation. This functional versatility is supported by a shared structural architecture that enables selective ion conduction and, in some members, regulated phospholipid scrambling. This review proposes a unifying framework in which anoctamin and transmembrane channel-like proteins act as multimodal regulators of sensory signaling, linking environmental cues to cellular excitability and microenvironmental control and highlighting new principles of chemosensory organization and therapeutic potential.